The Monitoring Process

- An Overview -
Monitoring: Definition
Act of overseeing
–progress of a clinical trial and
–ensuring that it is conducted, recorded and reported in
accordance with
protocol
SOPs
GCPs and
applicable regulatory requirements.
ICH Guideline 1.38

Rationale for Monitoring

Protection of human subjects’ rights and well-being.
Accuracy, completeness and verification of reported
trial data.
The people equation
Who does monitoring ?
Monitors/CRAs
–Appointed by sponsor
–Appropriately qualified and trained
–Should have scientific and/or clinical knowledge
–Familiar with investigational drug, protocol, ICF, SOPs, GCP, and
applicable regulatory requirements

ICH guidelines 5.18.2

SMART Monitor
S = Spokesperson

M = Manager

A = Auditor
R = Reporter

T = Trainer or traveller

Skills for CRA

Messenger
Organizer
Negotiator
Inspector
Trainer
Observer
Reporter

Stages of a Monitoring Visit

Before the visit

During the visit

After the visit

Before The Visit
The monitor will:
–Contact site to schedule the visit.
–Issue confirmation letter or e-mail.

During The Visit

The monitor will assess / discuss:
–Site, staffing, research lab facilities.
–Regulatory files and study records.
–Any problems and issues identified.
–Clinical procedures if possible/ appropriate.
–Conduct debriefing meeting at end of visit.
After The Visit
The monitor will:
 –complete site visit report.
–submit the report to sponsor.

The sponsor will:

–distribute site visit report and/or
cover letter to the site.

After The Visit (cont.)

The site should implement corrective actions based
on monitoring visit / cover letter.
The monitor will review corrective action, outlined in
the cover letter, during the next site visit.
4 Types of Site Visits
Site Assessment (Pre-study) Visit
Site Initiation Visit
Interim Site Visit
Close Out Visit
Site Assessment
Purpose:
To evaluate a site’s / investigator’s resources and
capabilities to conduct a research study.
Site Assessment (cont.)
The following will be assessed:
–Site infrastructure (staff and facilities) for the capability to conduct
the study.
–Adequacy and availability of site facilities for study conduct (e.g.
pharmacy, lab, clinical unit, record storage area).
Site Assessment (cont.)
The monitor will tour the following facilities and report
findings:
–Waiting area.
–Clinical exam / treatment / inpatient rooms.
–Laboratory.
 –Study product storage area.
–Office space.
Site Initiation Visit
Purpose:
–To uniformly provide study-specific information to investigator(s)
and staff prior to study start-up.

–To reassess resources and capability to conduct a research

study.
Site Initiation Visit (cont.)

The monitor will meet with the clinical staff to discuss

research obligations under GCP
[ICH Guidelines (ICH E6)]
–Investigator administrative responsibilities.
–IRB/IEC approvals and communication.
–Regulatory file requirements
(ICH E6 – 8.2 Essential Documents).
Site Initiation Visit (cont.)

–Informed consent forms and process.

–Protocol and protocol amendments.
–Source documentation.
–Study product handling and accountability.
–AE / SAE reporting.
–Protocol-specific training.
–Role of the clinical monitor.
–Record retention.
Site Initiation Visit (cont.)

The monitor will:

–Review sponsor policies, standards, and procedures for the
conduct of clinical trials.
–Reassess the site facilities.
 –Provide additional guidance to the site as determined by his/her
findings.
Site Monitoring Visit
Purpose:
Protection of human subjects’ rights and well-being.
Accuracy, completeness and verification of reported trial data.
Trial conduct in compliance with protocol/ amendments, Good
Clinical Practice (GCP), and regulatory requirement(s).
Site Monitoring Visit (cont.)
Assessment of Investigator’s Files.
Study Product Accountability.
Protocol-Specific Record Review.
Research Laboratory Assessment.
Observation of Clinical Operations.
Follow-up on Previously Identified Issues.
Debriefing Meeting at End of Visit.
Assessment of Investigator’s Files

–All protocol versions, amendments, and consents.

–All Institutional Review Board/ International Ethics Committee
(IRB/IEC) approvals.
–Investigator Brochure, if applicable.
–Versions / dates of procedure manuals.
–Continuing IRB/IEC review.
–List of all SAE reports and
safety reports.
–Specific lab normals (safety labs).
Assessment of Regulatory Files
(ICH E-6 8.2, 8.3 Essential Documents)
–Specific lab certifications and expiration dates.
–List of study staff CVs.
–Study personnel signature/initial sheet.
–Study personnel responsibility list and delegation of
responsibilities list
(should include anyone who enters data on source documentation and/or
CRFs).
–Previous monitoring reports and monitoring log.
Study Product Accountability
–Review of study product accountability documents, e.g.
Shipping receipts
–Verification of accountability
Comparison of accountability
record with actual, physical count
–Assessment of study product storage and handling, e.g.
Verification of cold chain maintenance
Temperature control of pharmacy

Protocol-Specific Record Review

–Informed Consent.
–Enrollment (inclusion/exclusion criteria).
–Adequacy of Source Documentation
(as per DMID Source
Documentation Guidelines).
–Timing of AE/SAE Reporting.
–Missed Visits.
–Protocol Violations and Deviations.
Informed Consent Checks
The approved informed consent form(s) (including
Pharmacogenetics) were
–appropriately obtained, signed and dated by each
subject/representative, prior to the start of any study specific
procedure
–signed and dated by the person who conducted the informed
consent discussion
–retained for each subject with the site study records
Research Laboratory Assessment
–Protocol related tests conducted by this lab.
–Details of sample collection.
–Sample flow from collection to lab.
–Data flow from lab report to CRF.
–Location of sample processing/analysis.
(On/Off site?)
Research Laboratory Assessment (cont.)
–Assess sample labeling, tracking, and storage.
–Observation of specimen storage area.
–Freezers:
E.g. presence of daily freezer temperatures log
 E.g. presence of auxiliary power
–Assessment of SOPs for lab procedures, maintenance, and
equipment.
Laboratory Samples cont’d
Regularly check for changes in local lab. reference ranges,
submit revisions to data management either electronically or
using the standard GSK form for reference ranges, file a
copy in site file
If a central laboratory is used, ensure investigator has any
revised ref. ranges
CRF Review
Check all SAEs, pregnancies and device incidents are
documented and reported

Collect, or arrange collection of, all reviewed and

completed CRF data/DQs for delivery to designated data
management centre within agreed timelines
CRF Review
eDM- check data has been submitted appropriately
Review agreed data entry/query resolution timelines
Resolve outstanding DQs and submit response
Original diary cards and other subject-completed forms should
remain with site study records whenever possible. When this is not
possible a certified (signed/dated by investigator or designate) copy
or transcription will remain at site

CRF Review and SDV

CRF Review
An overall review of the CRF for internal consistency,
completeness, logic and legibility

SDV
Verifying CRF data against information in supporting
documentation held at the site
CRF Review
Check consistency, completeness, logic, legibility,
adherence to protocol
Check all SAEs, pregnancies, and medical device
incidents are documented/reported
Check missed visits, tests/examinations not done, etc. are
documented
All paper CRF pages are accounted for and have accurate
identifiers (headers)
CRF Review cont.
No blank fields
Data written e.g. in margins is captured
New SAE information is followed up
Send reviewed/completed CRFs to data management,
resolve any DQs, submit answers, file DQs with the CRF
Note CRF review in MVR and any follow up on queries

Typical errors in the CRF

Some boxes left blank
DOB year = 2005
Ticked female but not completed contraception
Ticked on oral contraception but OC not entered on con
med page
AEs and con meds in notes but not entered into the CRF
Ticked for concurrent disorders (eg asthma) but no con
meds completed
CRF Corrections
Check corrections by site staff (on SSSS), in accordance
with the current SOP
Draw a single line through the incorrect entry
Do not use correction fluid
Do not ‘write over’, erase, or highlight
Enter correct data nearby
Date and initial corrections
Reason given if appropriate (justify if unusual or important correction)
Other Monitoring Activities
Ensure site staff are not entering info. on pharmacogenetics in
subject’s medical records

Sign and date the Site Visit Record with a member of the site staff
(as per the SSSS)

Address any other issues and corrective actions required

Observation of Clinical Operations
Observation of clinical operations when appropriate AND with
participant’s consent
–Informed consent process.
–Screening and enrolling process.
–Administration of study product.
–Obtaining laboratory samples.
Follow-up on Previously
Identified Issues
The monitor will attempt to
resolve previously identified
issues during this visit to
the extent possible, e.g.
–Informed consent issues.
–Outstanding corrections on forms.
–Missing documents in the
regulatory files.
Debriefing Meeting
–The pre-visit letter will request time for a debriefing meeting
–At least Investigator and Study Coordinator should be present.
–Monitor findings will be presented and discussed.
–The monitor may recommend re-training to research staff for
some identified issues.
Close Out Site Visit
The monitor ensures the following:
–IRB notified in writing of study completion/ withdrawal.
–Appropriate accounting and disposition of study product and
other study supplies completed.
 –Planned future use of remaining stored laboratory samples
determined and appropriate.
–Final report submitted to IRB/IEC and sponsor.
Close Out Site Visit (cont.)

The monitor will:

–Obtain copies of all study product shipping, receiving, and
accountability records for submission to sponsor.
–Remind the PI of his/her responsibility to maintain research files
until directed otherwise, in writing, by the sponsor
(ICH E6 – 8.2, 8.3, 8.4, Essential Documents).
–Record plan for disposition of CRFs.
2 Types of Monitoring
Internal Monitoring
(Study staff, site SOPs)
- Quality Management Process

External Monitoring
(Monitoring Contractor)
- Provides objectivity in the validation of data
Here Comes the Monitor…
 Common goal for site and sponsor:
–Protection of human subjects’ rights and well-being.
–Accuracy, completeness and verification of reported trial data.
–Trial conduct in compliance with protocol/ amendments, Good
Clinical Practice (GCP), and regulatory requirement(s).
Enjoy & wishing U all the best for
Monitoring